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Acute Thrombolytic Therapy

5th Edition
2015 UPDATE
June 2015

The Canadian Stroke Best Practice Recommendations for Hyperacute Stroke Care, 5th Edition (2015) is published in the International Journal of Stroke (IJS) and available freely online. To access the specific recommendations for Acute Thrombolytic Therapy and all other sections of the Hyperacute Stroke Care recommendations, please click on this URL which will take you to the recommendations online in the IJS: http://onlinelibrary.wiley.com/doi/10.1111/ijs.12551/full

For the French version of these recommendations, open the appendix at this link :  http://onlinelibrary.wiley.com/store/10.1111/ijs.12551/asset/supinfo/ijs12551-sup-0001-si.zip?v=1&s=cdf3d494242426450aaa522f104ace17857f037a

All other supporting information, including performance measures, implementation resources, evidence summaries and references, remain available through www.strokebestpractices.ca, and not through the IJS.  Please click on the appropriate sections on our website below for this additional content.

Box 4.3: Endovascular Imaging Selection Criteria

Principles of imaging selection Use imaging to select patients for treatment who have all 3 of the following:

  1. A small-to-moderate ischemic core.
    1. A small-to-moderate ischemic core is defined by an ASPECTS score of 6 or higher on non-contrast computed tomography (NCCT) or cerebral blood volume (CBV) map on CT perfusion imaging.
  2. An occluded proximal intracranial artery of the anterior circulation, which is a target lesion amenable to endovascular therapy.
    1. The location of occlusion is defined by an arterial phase CTA from ascending aorta to the vertex of the head. Inclusion of the aortic structures allows planning and assessment of the technical feasibility of an endovascular approach to the occluded intracranial artery.
  3. Evidence of moderate-to-good pial collateral filling defined by multi-phase or dynamic CTA, or evidence of CT perfusion mismatch. Refer to Summary Table: Comparison of Key Elements of Recent Endovascular Clinical Trials.

 

Rationale

Meta-analyses of the randomized controlled trials of intravenous tPA for acute ischemic stroke have shown that thrombolytic treatment can reduce the risk of disability and death, despite the risk of serious bleeding. The latest time for tPA administration after stroke onset remains imprecisely defined, but currently available data show clear evidence of benefit when given up to 4.5 hours after the onset of symptoms. The available evidence demonstrates a strong inverse relationship between treatment delay and clinical outcome; eligible patients should be treated without delay, regardless of when they present within the treatment window.

Endovascular treatment for large artery ischemic stroke has clearly demonstrated efficacy with numbers needed to treat of approximately four to achieve functional independence at 90 days. This therapy has profound impact on patients who suffer the most devastating ischemic strokes; patients who, if left untreated, will place a more significant burden on the healthcare system and family caregivers.

System Implications

  • Local protocols should prioritize stroke patients for immediate access to appropriate diagnostics such as CT imaging and neurovascular imaging with CTA. This should include patients with known times of stroke symptom onset (or time last seen well), and patients who are discovered with stroke symptoms on wakening.
  • Availability of helical CT scanners with appropriate programming for CT angiography (multiphase or dynamic CTA) and CT perfusion sequences, and appropriate post-processing software optimized for the production of high-quality imaging.
  • Coordinated and integrated systems of care involving all relevant personnel in the hyperacute care of stroke patients, including paramedics, emergency department staff, stroke teams, radiologists and neurointerventionists. Protocols should be in place in partnership with EMS agencies and treating hospitals, and between hospitals within stroke systems to ensure rapid transport to centres providing advanced stroke services within treatment time windows.
  • Stroke neurology and neurointerventional expertise should be regionalized, with a system in place across regions for rapid access to physicians experienced in acute thrombolysis and endovascular therapies, including through telemedicine. This includes protocols for contacting physicians with stroke expertise for administration of intravenous tPA, as well as transport to higher levels of stroke care, as needed, for intravenous tPA or endovascular therapy.
  • Hyperacute protocols in place and well-communicated to all healthcare practitioners within the hospital regarding management of in-hospital stroke patients, ensuring access to CT imaging of the brain and CTA of the extracranial and intracranial vessels as soon as possible after stroke symptom onset.
  • Access to specialized stroke units where staff are experienced in managing patients who have received tPA or endovascular therapy.
  • Endovascular interventional programs are in evolution across Canada; decisions around appropriate site, transfer protocols, timelines will be determined at the provincial or regional level.  Decisions about when those services are fully operational, and who should be transferred by paramedics to those facilities should be made at the provincial/regional level and communicated to all relevant stakeholders.

Performance Measures

  1. Overall proportion of all ischemic stroke patients who receive treatment with intravenous tPA (core).
  2. Median time (in minutes) from patient arrival in the emergency department to administration of intravenous tPA.
  3. Median time from hospital arrival to groin puncture, and from CT scan (first slice of the non-contrast CT) to groin puncture for patients undergoing endovascular therapy.
  4. Proportion of ischemic stroke patients who receive treatment with intravenous tPA within 3.0 and 4.5 hours of symptom onset.
  5. Proportion of all thrombolyzed stroke patients who receive tPA within 30 minutes of hospital arrival (core).
  6. Overall proportion of all ischemic stroke patients who receive treatment with endovascular therapy (core).
  7. Median time from hospital arrival to reperfusion for patients undergoing endovascular therapy. Time of reperfusion should be defined as the first angiographic image showing partial or complete reperfusion of the affected arterial territory. In many cases, this will coincide with the first deployment of a retrievable stent.
  8. For patients with stroke while in hospital for other medical reasons (in-hospital strokes), median time from last known well to brain imaging.
  9. For patients with stroke while in hospital for other medical reasons (in-hospital strokes), median time from last known well to acute thrombolysis or endovascular therapy (groin puncture).
  10. Final reperfusion status for patients undergoing endovascular reperfusion therapy, quantified using the modified Thrombolysis in Cerebral Infarction (mTICI) system.
  11. Proportion of patients with symptomatic subarachnoid or intracerebral hemorrhage following intravenous tPA (defined as any PH1, PH2, RIH, SAH, or IVH associated with a four-point or more worsening on the NIHSS within 24 hours).
  12. Proportion of patients with symptomatic subarachnoid or intracerebral hemorrhage following endovascular therapy (defined as any PH1, PH2, RIH, SAH, or IVH associated with a four-point or more worsening on the NIHSS within 24 hours).
  13. Proportion of patients in rural or remote communities who receive tPA through the use of telestroke technology (as a proportion of all ischemic stroke patients in that community and as a proportion of all telestroke consults for ischemic stroke).
  14. Modified Rankin Scale (mRS) score of all stroke patients who receive intravenous tPA or endovascular therapy at time of hospital discharge and at 90 days post-hospital discharge.
  15. In-hospital mortality rates (overall and 30-day) for ischemic stroke patients stratified by those who receive tPA or endovascular therapy and those who do not.

Measurement Notes

  • Data may be obtained from patient charts, through chart audit or review.
  • Time interval measurements should be taken from the time the patient is triaged or registered at the hospital (whichever time comes first) until the time of tPA administration noted in the patient chart (nursing notes, emergency department record, or medication record).
  • For performance measures 4 and 5, calculate all percentiles and examine 50th and 90th percentiles and inter-quartile range.
  • When recording if tPA is given, the route of administration should also be recorded, as there are different times to administration benchmarks for intravenous and endovascular routes
  • For endovascular therapy, treatment time should be time of first groin puncture.

Implementation Resources and Knowledge Transfer Tools

Health Care Provider Information

Patient Information

Summary of the Evidence

Evidence Table 4A Acute Thrombolytic Therapy

Evidence Table 4B Endovascular Therapy

Section 4 Comparison of Endovascular Treatment Trials

The weight of evidence from many large, international trials over a time frame of 20 years suggests that treatment with intravenous tissue Plasminogen Activator (tPA) can reduce the risk of death or disability following ischemic stroke at 3 to 6 months post-treatment. Since the fall of 2014, five major clinical trials of endovascular therapy with mechanical embolectomy were completed with results demonstrating significant improvement in patient outcomes based on the modified Rankin scale score at 90 days post-treatment, with one trial also demonstrating decreased mortality with endovascular therapy (Goyal et al, 2015; Campbell et al. 2015; Berkhemer et al, 2014; Saver et al, 2015, Davalos et al 2015).

Intravenous Thrombolysis

The NINDS trial (1995) was one of the earliest, large trials, which was conducted in the USA. Patients were randomized to receive Alteplase or placebo within 3 hours of symptom onset. At 3 months, significantly more patients in the t-PA group had experienced a good outcome (using any one of the study’s 4 metrics), with no difference in 90-day mortality between groups. In contrast, patients who received Alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group.

In the first ECASS trial (1995) 620 patients received Alteplase or placebo within 6 hours of event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the Alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with Alteplase and placebo were 40.3% vs. 36.6%, respectively, absolute difference =3.7%, p=0.277. In subgroup analysis of patients treated < 3 hours and 3-6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%. Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the Alteplase group experienced a favourable outcome, defined as mRS scores <2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the Alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009). At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic ICH associated with treatment with Alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality.

The Third International Stroke Trial (2012), is the largest (n=3,035) and most recent trial of Alteplase, in which patients were randomized to receive a standard dose of Alteplase (0.9 mg/kg) or placebo. Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and to determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advance age or time to treatment. Unlike all previous, large trials, which excluded them, IST-3 included patients >80 years. In fact, the majority of patients (53%) were >80 years. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received Alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with Alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the sub groups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the t-PA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001).

Although it is known that the optimal timing of administration of intravenous Alteplase is <3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the 3-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous Alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002-2007 to compare the outcomes of patients who had been treated with Alteplase within 3 hour of symptom onset (n=11,865) and those treated from 3-4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the 3-hour treatment window. Patients in the <3 hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of Alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3-4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). A meta-analysis restricted to RCTs patients from the ECASS I, II and III and ATLANTIS trials (n=1,622) who had received Alteplase or placebo 3 to 4.5 hours following stroke suggested a benefit of treatment (Lansberg et al. 2009). Patients who had received Alteplase had a significantly greater likelihood of a favourable outcome (OR=1.31, 95% CI 1.1-1.56, p=0.002) and were no more likely to be dead at 90 days. OR=1.01, 95% CI 0.75-1.43, p=0.83). Outcome data for ICH were not reported. Most recently, Emberson et al. (2014) used data from 6,756 patients from 9 major t-PA trials (NINDs a/b, ECASS I/II,III, ATLANTIS a/b, EPITHET, IST-3)to more closely examine the effect of timing of administration. Earlier treatment was associated with the increased odds of a good outcome, defined as an (mRS score of 0-1 ( ≤3.0 h: OR=1.75, 95% CI 1.35-2.27 vs. >3 to ≤4.5 h: OR=1.26, 95% CI 1.05-1051 vs. >4.5 h: OR=1.15, 95% CI 0.95-1.40).

An updated systematic review and meta-analysis of intravenous thrombolysis (Wardlaw et al. 2013) that included the results from 12 RCTs (7,012 patients), published from 1992-2012 strengthen the evidence that treatment with t-PA is safe and effective. The authors concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective.

The use of thrombolytic therapy in patients who are younger than 18 years and in women at any stage of pregnancy has not been evaluated empirically. Twelve case reports of women who received thrombolysis treatment constitute the evidence base for this group. The results from 11 cases have been summarized by Li et al. (2012) and the 12th case report was published recently (Tassi et al. 2013). In 4 cases, t-PA was administered using the intra-arterial route. The neurological outcomes of these women were described as being similar to (non-pregnant) patients who met the eligibility criteria. The evidence in terms of thrombolytic treatment for patients <18 years comes primarily from the International Pediatric Stroke Study, (IPSS) an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial Alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died and the remainder had moderate or severe neurological deficits. The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al. 2009) is currently recruiting subjects for 5-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial t-PA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.

The results of a recent feasibility study, TEMPO-1 (Coutts et al. 2015), suggest that Tenecteplase (TNK-tissue-type plasminogen activator) may be a safe and effective treatment for minor stroke and TIA. In this open-label study, 55 patients, previously independent with NIHSS score ≤5 with an event occurring within the previous 12 hours, received a single dose of intravenous TNK-t-PA of 0.1 mg/kg or 0.25 mg/kg. The incidence of symptomatic ICH and mortality were low, while 46% of all patients treated experienced complete recanalization at 24 hours following treatment and 90% experienced a good outcome (mRS 0-2) at 90 days.

Intra-arterial Thrombolysis & Endovascular Therapy

Re-vascularization can also be achieved through intra-arterial administration of thrombolytic agents or mechanical dislodgement with specialized devices. The body of evidence for these procedures is not as well developed as it is for intravenous thrombolysis. A meta-analysis (Fargen et al. 2014) included the results of 6 RCTs (PROACT II, MELT, IMS III, SYNTHESIS, MR. RESCUE and MR. CLEAN, n=1,903) comparing endovascular therapies with best medical management following ischemic stroke. Using the results from 5 studies that included patients with large-vessel occlusions, endovascular therapy was associated with significantly improved odds of a good (mRS 0-2) and excellent (mRS 0-1) recovery at 90 days (OR=1.67, 95% CI 1.29-2.16, and OR=1.93, 95% CI 1.39-2.68, respectively. There was also a positive shift in mRS scores (mean 3.35 vs. 3.73, p<0.0001), but no significant decrease in mortality (OR=0.80, 95% CI 0.60-1.07). When all 6 trials were included, the pattern of results was similar, although the odds of an excellent recovery were not significantly improved (OR=1.22, 95% CI 0.97-1.53).

The recent results from 5 multi-centered RCTs suggest that rapid endovascular therapy may be a safe and more effective treatment than intravenous t-PA only for patients with anterior circulation ischemic strokes in selected regions when performed within 6-12 hours of symptom onset. In the largest of these trials, MR CLEAN (Berkhemer et al. 2014), and the only one which was not stopped early due to efficacy, 500 patients were recruited who were ≥18 years, with a baseline NIHSS score of 2 or greater, and were treatable within 6 hours of stroke onset. Patients were randomized to receive endovascular treatment with t-PA or urokinase, and/or mechanical treatment with retrievable stents or other available devices or best medical management only, which could include intravenous t-PA. Retrievable stents were used in 81.5% of patients assigned to the endovascular therapy group. The median time from stroke onset to groin puncture was 260 minutes. The majority of patients in both groups were treated with intravenous t-PA (87.1% intervention group, 90.6% control group). There was a significant shift in the distribution towards more favourable mRS scores among patients in the intervention group at 90 days (adj common OR=1.67, 95% CI 1.21-2.30). The odds of both a good (mRS 0-2) and excellent (mRS 0-1) recovery at day 90 were also significantly higher among patients in the intervention group (adj OR=2.07, 95% CI 1.07-4.02 and adj OR=2.16, 95% CIU 1.39-3.38, respectively). Patients in the intervention group were more likely to show no evidence of intracranial occlusion on follow-up CTA (adj OR=6.88, 95% CI 4.34-10.94, n=394) and to have a lower median final infarct volume (-19 mL, 95% CI 3-34, n=298).

The ESCAPE trial (Goyal et al. 2015) enrolled 316 patients ≥18 years, with stroke onset less than 12 hours, a baseline NIHSS score of > 5 and moderate-to-good collateral circulation. Patients were randomized to receive endovascular mechanical thrombectomy, using available devices or best medical management. The median time from stroke onset to first reperfusion was 241 minutes. 72.7% of patients in the intervention group and 78.7% of those in the control group received intravenous t-PA. The odds of improvement in mRS scores by 1 point at 90 days were significantly higher among patients in the intervention group (adj OR=3.2, 95% CI 2.0-4.7). The odds of good outcome (mRS score 0-2) at 90 days were also higher in the intervention group (adj OR=1.7, 95% CI 1.3-2.2), as were the odds of a NIHSS score of 0-2 and a Barthel Index score of 95-100 (adj OR=2.1, 95% CI 1.5-3.0 and 1.7, 95% CI 1.3-2.22, respectively). The risk of death was significantly lower in the intervention group (adj RR=0.5, 95% CI 0.-0.8). In neither MR CLEAN nor ESCAPE, was there an increased risk of symptomatic ICH associated with endovascular therapy. No interaction effects were found in subgroup analyses of age, stroke severity, time to randomization, or baseline ASPECTS in either of the trials.

Three trials evaluated the efficacy of the use of a specific device for clot retrieval (Solitaire FR Revascularization Device). In the EXTEND IA trial (Campbell et al. 2015), there were no inclusion criteria related to stroke severity. Seventy patients ≥18 years, with good premorbid function and an anterior circulation acute ischemic stroke, with criteria for mismatch, who could receive intra-arterial treatment within 6 hours of stroke onset, were included. All patients received intravenous t-PA, while 35 also underwent intra-arterial mechanical clot retrieval. A significantly greater proportion of patients in the endovascular group experienced early neurological improvement (80% vs. 37%, p<0.001), >90% reperfusion without ICH at 24 hours (89% vs. 34%, p<0.001) and were functionally independent at day 90 (71% vs. 40%, p=0.009).

The SWIFT-PRIME trial randomized 196 patients, aged 18-80 years with NIHSS scores of 8-29 with a confirmed infarction located in the intracranial internal carotid artery, MCA, or carotid terminus who could be treated within 6 hours of onset of stroke symptom, to receive intravenous t-PA therapy + intra-arterial mechanical clot retrieval, or t-PA only. The likelihood of successful reperfusion (>90%) at 27 hours was significantly higher in the endovascular therapy group (82.8% vs. 40.4%, RR=2.05, 95% CI 1.45-2.91, p<0.001) and a significantly higher percentage of patients were independent at day 90 (mRS 0-2) (60.2% vs. 35.5%, RR=1.70, 95% CI 1.23-2.33, p=0.001).

Finally, in the REVASCAT trial (Jovin et al. 2015), 206 patients with NIHSS scores of 6 or greater who could be treated within 8 hours of stroke onset were randomized to receive mechanical embolectomy + best medical management or best medical management only, which could include intravenous t-PA. The odds of dramatic neurological improvement at 24 hours were increased significantly in the intervention group (adj OR=5.8, 95% CI 3.0-11.1). The odds for improvement by 1 mRS point at 90 days were increased significantly in the intervention group (adj OR=1.7, 95% CI 1.05-2.8), as were the odds of achieving an mRS score of 0-2 at 90 days (adj OR=2.1, 95% CI 1.1-4.0). No treatment effects were noted based on sub group analyses in either SWIFT-PRIME or REVASCAT, based on age, baseline NIHSS score, site of occlusion, time to randomization, or ASPECTS score. There was no increased risk of symptomatic ICH in any of these trials.

The positive results from these 5 trials contrast with those of earlier RCTs examining endovascular therapy. In the SYNTHESIS trial, Ciccone et al. (2013) randomized 362 patients to receive either pharmacological or mechanical thrombolysis, or a combination of these approaches or intravenous t-PA within 4.5 hours of symptom onset. At 90 days, the percentages of patients alive, living without disability were similar between groups (30.4% vs. 34.8%, adjusted OR=0.71, 95% CI 0.44 to 1.14, p=0.16). There were no differences in adverse events between groups (death or ICH). The IMS III trial (Broderick et al. 2013), which also randomized patients to receive mechanical or pharmacological endovascular treatment, or intravenous t-PA was stopped early due to a lack of efficacy. Reasons that have been cited for the lack of positive findings in these trials include the use of older style devices, the prolonged time to initiation of intra-arterial treatment and the lack of pre-treatment vascular imaging. The hypothesis that patients with a favorable penumbral pattern, may benefit preferentially from endovascular treatment compared with those with a nonpenumbral pattern was not supported in the MR RESCUE trial (Kidwell et al. 2013). Patients were randomized within 8 hours of symptom onset to undergo mechanical embolectomy with the Merci Retriever or Penumbra System, or standard care, grouped according to penumbra pattern vs. nonpenumbra pattern. At 90 days, there were no significant differences between groups (embolectomy vs. standard care) in the mean mRS score, the proportion of patients with a good outcome (mRS 0-2) or death among patients with penumbral or nonpenumbral patterns. The authors suggested that the low rates of recanalization may have been one of the contributors to the null findings.